The advanced biopharmaceutical application of cocrystal

Poor aqueous solubility remains a major challenge in drug development, particularly for Biopharmaceutics Classification System (BCS) class II drugs, whose absorption is limited by solubility and dissolution rate. For BCS class IV drugs, which are additionally restricted by permeability, the benefit of solubility enhancement is less predictable. Pharmaceutical cocrystals are a promising and innovative solid-state approach to improve the biopharmaceutical properties of active pharmaceutical ingredients (APIs) without changing their intrinsic chemical structure and pharmacological identity. This review systematically examines the basic design concepts, the wide range of therapeutic applications, and the mechanism of dissolution enhancement and bioavailability improvement of cocrystals. We discuss the integration of cocrystals into synergistic combination therapies, stimuli-responsive smart delivery systems, and advanced nanoscale formulations that enable targeted and controlled drug release. Despite this, there are significant challenges remaining, such as physiological instability in the gastrointestinal tract, manufacturing scalability and reproducibility, rational coformer selection strategies, and regulatory uncertainty exacerbated by sparse pharmacokinetic information and a lack of understanding regarding cocrystal biological interactions at a molecular level. Bringing cocrystal-based formulations to clinical use will take joint, multidisciplinary, and solution-driven efforts across the disciplines of pharmaceutical sciences, materials chemistry, regulatory science, and clinical pharmacology. Finally, pharmaceutical cocrystals represent a promising platform to address solubility restrictions, with growing evidence, predominantly preclinical, of improved therapeutic performance for poorly soluble drugs.